Conditional Deletion of PTHrP in Articular Chondrocytes

我们已经创建了PTHrP-lacZ基因敲入小鼠，其作为敏感的 PTHrP基因表达系统。这只老鼠的研究结果表明， 对PTHrP在软骨内骨中的功能的解释可能需要改进。 软骨骨骺（CE）是下丘脑的原始骨骺生长区， 也是驱动线性生长的结构， 陆地哺乳动物的胚胎发生。CE的增殖软骨细胞 表达PTHrP，这是产前发育的这一阶段， 几乎只在出版的作品中。在小鼠出生后第7-10天， 次级骨化中心形成并细分表达PTHrP的软骨细胞 分为两个亚群，一个与生长板有关，另一个将 成为关节软骨细胞（AC）。表达PTH-1受体的前肥大细胞 软骨细胞以一种 排除了来自AC和关节间隙的矿化肥大软骨细胞。PTHrP AC中的表达是负荷依赖性的，并且体内卸载关节导致抑制 在PTHrP/β gal表达和肥大软骨细胞大量增加中， 接近关节面。 我们建议在这里有条件地删除PTHrP在AC使用Gdf 5-Cre小鼠。 该系统将允许详细研究PTHrP正常 在AC中起调节软骨细胞分化程序的作用， 其他地方该系统还可以提供有价值的骨关节炎小鼠模型。

We have created a PTHrP-lacZ knock-in mouse, which serves as a sensitive PTHrP gene expression system. Findings in this mouse suggest that existing interpretations as to PTHrP functions in endochondral bone may need to be refined. The chondroepiphysis (CE) is the primordial epiphyseal growth zone in lower forms such as teleosts and is also the structure that drives linear growth during embryogenesis in terrestrial mammals. The proliferative chondrocytes of the CE express PTHrP, and it is this stage of prenatal development that has been focused upon almost exclusively in the published work. At postnatal day 7-10 in the mouse, the secondary ossification center forms and subdivides the PTHrP-expressing chondrocytes into two subpopulations, one associated with the growth plate and a second that will become articular chondrocytes (AC). The PTH-1 receptor-expressing prehypertrophic chondrocytes lie immediately subjacent to the PTHrP-expressing ACs, in a fashion that excludes mineralizing hypertrophic chondrocytes from the ACs and joint space. PTHrP expression in ACs is load-depend, and unloading a joint in vivo leads to a suppression in PTHrP/(3 gal expression and a large increase in hypertrophic chondrocytes that approach the articular surface. We propose here to conditionally delete PTHrP in ACs using a Gdf5-Cre mouse. This system will allow a detailed study of the working hypothesis that PTHrP normally functions to regulate the chondrocyte differentiation program in ACs, as it does elsewhere. The system may also provide a valuable mouse model of osteoarthritis.